The present invention relates to methods of administering aminoalkyl phosphorothioate and/or aminoalkyl thiol compounds to a subject in a manner that reduces or decreases the undesirable side effects of the compounds. One aspect of the invention relates to the subcutaneous administration of amifostine and/or its active metabolite to a patient, which reduces adverse side effects. Another aspect of the invention relates to methods of administering amifostine and/or its active metabolite to a patient in a manner such that a characteristic pharmacokinetic profile is obtained. When administered according to the characteristic pharmacokinetic profile, fewer adverse side effects are experienced by patients.
Amifostine (also known as WR-2721) has been shown to be useful as a radiation protectant in cancer patients receiving radiation therapy (Constine et al., 1986, xe2x80x9cProtection by WR-2721 of Human Bone Marrow Function Following Irradiationxe2x80x9d Int. J. Radia. Oncol. Biol. Phys. 12:1505-8; Liu et al., 1992, xe2x80x9cUse of Radiation with or Without WR-2721 in Advanced Rectal Cancerxe2x80x9d Cancer 69(11):2820-5; Wadler et al., 1993, xe2x80x9cPilot Trial of Cisplatin, Radiation and WR-2721 in Carcinoma of the Uterine Cervix: A New York Gynecologic Oncology Group Studyxe2x80x9d J. Clin. Oncol. 11(8):1511-6; Buntzel et al., 1996, xe2x80x9cSelective Cytoprotection with Amifostine in Simultaneous Radiochemotherapy of Head Neck Cancerxe2x80x9d Ann. Oncol. 7(Suppl.5):81(381P)). Amifostine is a pro-drug that is dephosphorylated at the tissue site by alkaline phosphatase to the free thiol, which is the active metabolite (also known as WR-1065). Once inside the cell, the active free thiol can protect against the toxicities associated with radiation by acting as a scavenger for oxygen free-radicals that are produced by ionizing radiation (Yuhas, 1977, xe2x80x9cOn the Potential Application of Radioprotective Drugs in Solid Tumor Radiotherapy,xe2x80x9d In: Radiation-Drug Interactions in Cancer Management pp. 303-52; Yuhas, 1973, xe2x80x9cRadiotherapy of Experimental Lung Tumors in the Presence and Absence of a Radioprotective Drug S-2-(3-Aminopropylamino) thylphosphorothioc Acid (WR-2721)xe2x80x9d J. Natl. Cancer Inst. 50:69-78; Philips et al., 1984, xe2x80x9cPromise of Radiosensitizers and Radioprotectors in the Treatment of Human Cancerxe2x80x9d Cancer Treat. Rep. 68:291-302).
Amifostine""s ability to selectively protect normal tissues is based on the differential metabolism and uptake of amifostine into normal tissue versus tumor tissue. Amifostine is rapidly taken up and retained in normal tissues. Differences in capillary and membrane-bound alkaline phosphatase concentration and pH between normal and tumor tissues have been shown to favor the conversion of the pro-drug and uptake of the active form of amifostine, the free thiol, into normal tissues. Coupled with the fact that normal cells concentrate the free thiol at a faster rate than tumors and retain it for longer periods of time, amifostine is able to selectively protect normal tissues against the toxicities associated with radiation without negatively affecting the antitumor response. The marked differences in tissue uptake and retention between normal and tumor tissues produces a temporary state of acquired drug resistance in normal tissues, analogous to that produced by an excess of endogenous glutathione.
For a cytoprotector to be useful in radiation therapy, the compound must be tolerated on a daily basis, up to 4 or 5 days a week for several weeks, prior to the delivery of conventional doses of radiation. McDonald et al. (McDonald, 1994, xe2x80x9cPreliminary Results of a Pilot Study Using WR-2721 Before Fractionated Irradiation of Head and Neck to Reduce Salivary Gland Dysfunctionxe2x80x9d Int. J. Radiat. Oncol. Biol. Phys. 29(4):747-54; McDonald et al., 1995, xe2x80x9cAmifostine Preserves the Salivary Gland Function During Irradiation of the Head and Neckxe2x80x9d Eur. J. Cancer 31a(Supp. 5):415) have conducted a dose-escalation study of amifostine and radiation in patients with head and neck cancer. These results suggest that daily administration of amifostine (200 mg/m2 via a 6-minute intravenous infusion) prior to radiation protects the salivary gland against the toxicities of radiation.
Amifostine has also been shown to stimulate bone marrow growth, and is currently in Phase II clinical trials as a bone marrow stimulant in patients suffering from myelodysplastic syndrome (List et al., 1996, xe2x80x9cAmifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trialxe2x80x9d Am. J. Hem. 1 (Abstract); List et al., 1996, xe2x80x9cAmifostine Promotes in vitro and in vivo Hematopoiesis in Myelodysplastic Syndromesxe2x80x9d Chem. Found Sympos. (Abstract); List et al., 1996, xe2x80x9cAmifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial,xe2x80x9d Abstract, 8th Annual Meeting, American Society of Hematology, Orlando, Fla.). In this study, amifostine is being administered via intravenous infusion.
Intravenous administration of amifostine suffers from several serious drawbacks. First, administering compounds intravenously is extremely inconvenient, particularly when a daily dosing schedule for several weeks, or potentially several months in the case of MDS, is necessary, requiring a skilled practitioner to administer the dose. Second, when administered intravenously, patients suffer from dose-dependent undesirable side-effects such as nausea, vomiting, emesis and hypotension, as well as flushing or feeling of warmth, chills or feeling of coldness, dizziness, somnolence, hiccups and sneezing. A decrease in serum calcium concentration is a known pharmacological effect of intravenously administered amifostine. Allergic reactions ranging from mild skin rashes to rigors have also rarely occurred in conjunction with intravenously administered amifostine. At present, there are no known methods, other than co-administering agents such as anti-emetics, of reducing or avoiding these undesirable side effects. Third, there are related costs associated with intravenous administration, including personnel, equipment and medical measures to attenuate side effects.
The human pharmacokinetic profile of amifostine has been investigated in cancer patients following a single intravenous bolus dose (150 mg/kg) (Shaw et al., 1986, xe2x80x9cHuman Pharmacokinetics of WR-2721xe2x80x9d Int. J. Radiat. Oncol. Biol. Phys. 12:1501-4), a single 15-minute intravenous infusion (up to 910 mg/m2) (Shaw et al., 1988, xe2x80x9cPharmacokinetics of WR-2721xe2x80x9d Pharmac. Ther. 39:195-201; Shaw et al., 1994, xe2x80x9cPharmacokinetics of Amifostine in Cancer Patients: Evidence for Saturable Metabolismxe2x80x9d Proc. Amer. Cos. Clin. Oncol. 13:144; U.S. Bioscience, 1994, xe2x80x9cPharmacokinetics of Single ose Amifostine (WR-2721; Ethyol)xe2x80x9d ETH PK 3) and repeated infusions (up to 910 mg/M2 per dose) (U.S. Bioscience, 1994, xe2x80x9cPharmacokinetics of Double Dose Amifostine (WR-2721; Ethyol) ith Corresponding Measurements of WR-1065 in Plasma and Bone arrow Cellsxe2x80x9d ETH PK 4). These studies showed that mifostine is rapidly cleared from the plasma with a distribution half-life of less than 1 minute and an elimination half-life of approximately 9 minutes. Less than 10% of amifostine remained in the plasma 6 minutes after intravenous administration. No previous human clinical harmacokinetic studies have been conducted using either orally or subcutaneously administered amifostine.
Tabachnik reported that the oral administration of amifostine reduced sputum viscosity in cystic fibrosis patients (Tabachnik et al., 1980, xe2x80x9cStudies on the Reduction of Sputum Viscosity in Cystic Fibrosis Using an Orally Absorbed Protected Thiol.xe2x80x9d J. Pharm. Exp. Ther. 214:246-9; Tabachnik et al., 1982, xe2x80x9cProtein Binding of N-2-Mercaptoethyl-1 3-Diaminopropane via Mixed Disulfide Formation After Oral Administration of WR-2721xe2x80x9d J. Pharm Exp. Ther. 220:243-6). However, these studies did not demonstrate that this mode of administration reduced adverse side effects commonly associated with intravenously administered amifostine. Furthermore, a study of the pharmacokinetic profile of the admnistered compounds was not conducted in these patients.
The present invention provides methods of administering aminoalkyl phosphorothioate and/or aminoalkyl thiol compounds to a subject, including humans, in a manner which decreases or reduces the undesirable side effects of the compounds. One aspect of the invention relates to the subcutaneous administration of an aminoalkyl phosphorothioate and/or aminoalkyl thiol compound to a human subject. Another aspect of the invention relates to the administration of an aminoalkyl phosphorothioate and/or aminoalkyl thiol compound to a patient in a manner such that a characteristic pharmacokinetic profile is obtained. The pharmacokinetic profile is generally characterized by a first region wherein the plasma and/or a whole blood concentration of administered compound, an active metabolite thereof, or both gradually increases to a maximum concentration, a second region wherein the maximum plasma and/or whole blood concentration is substantially maintained, or plateaus, and a third region wherein the plasma and/or whole blood concentration gradually decreases to baseline levels. The rate at which the plasma and/or whole blood concentration of the administered compound (and/or an active metabolite thereof) increases to the maximum level is markedly slower than that achieved with conventional intravenous administration.
Administering aminoalkyl phosphorothioate and/or aminoalkyl thiol compounds according to the methods of the invention significantly reduces or decreases the adverse or undesirable side effects suffered by patients as compared to conventional intravenous administration, without substantially affecting the efficacy of the applied dose. Thus, the methods of the invention can be advantageously used in conjunction with treatment strategies for delivering aminoalkyl phosphorothioate and/or aminoalkyl thiol compounds to patients without inducing the vomiting, nausea, emesis, hypotension or other undesirable side-effects, including but not limited to, flushing or feeling of warmth, chills or feeling of coldness, dizziness, somnolence, hiccups, sneezing, decreased serum calcium levels and allergic reactions that are commonly experienced with conventional intravenous administration.